Clinical Trials /

Tucatinib + Abemaciclib + Herceptin for HER2+ MBC

NCT03846583

Description:

This research study is studying a combination of drugs as a possible treatment for HER2-Postive Metastatic Breast Cancer. The interventions involved in this study are: - Tucatinib - Abemaciclib (VerzenioTM) - Trastuzumab (Herceptin®) - Endocrine Therapy: Exemestane (Aromasin®), Letrozole (Femara®), or Anastrozole (Arimidex®)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Tucatinib + Abemaciclib + Herceptin for HER2+ MBC
  • Official Title: Phase Ib Trial of Tucatinib in Combination With Abemaciclib and Trastuzumab for Patients With HER2-Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 18-621
  • NCT ID: NCT03846583

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
TucatinibDose Escalation
AbemaciclibVerzenioDose Escalation
TrastuzumabHerceptinDose Escalation
Aromatase InhibitorDose Escalation

Purpose

This research study is studying a combination of drugs as a possible treatment for HER2-Postive Metastatic Breast Cancer. The interventions involved in this study are: - Tucatinib - Abemaciclib (VerzenioTM) - Trastuzumab (Herceptin®) - Endocrine Therapy: Exemestane (Aromasin®), Letrozole (Femara®), or Anastrozole (Arimidex®)

Detailed Description

      This research study is a Phase Ib clinical trial, which tests the safety of an
      investigational intervention and also tries to define the appropriate dose of the
      investigational intervention to use for further studies. "Investigational" means that the
      intervention is being studied. The U.S. Food and Drug Administration (FDA) has not approved
      the combination of Tucatinib, Abemaciclib, and Trastuzumab as a treatment for any disease.

      In this research study, the investigators are:

        -  Studying the combination of Tucatinib, Abemaciclib, Trastuzumab, and hormonal therapy.

        -  Tucatinib is a drug that inhibits human epidermal growth factor receptor 2 (HER-2)
           protein, which is a protein expressed in the cancer cells. By inhibiting this protein,
           tucatinib may help stop or reduce the growth of the tumor. The U.S. Food and Drug
           Administration (FDA) has not approved Tucatinib as a treatment for any disease, but it
           has been used in a research setting with humans for many years.

        -  Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors work to stop
           cell growth. The FDA has not approved Abemaciclib for this specific disease, but it has
           been approved for other uses.

        -  Trastuzumab is called a "targeted therapy" because it works by attaching itself to
           specific receptors on the surface of breast cancer cells, known as HER2 receptors. When
           Trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are
           blocked and the cancer cell may be marked for destruction by your immune system. This
           process allows trastuzumab to help slow or stop the growth of the breast cancer. The FDA
           has approved Trastuzumab as a treatment for this disease.

        -  Exemestane, Letrozole, and Anastrozole belong to a class of drugs called aromatase
           inhibitors. the participant and the physician will choose the most appropriate aromatase
           inhibitor for them. These drugs act by lowering the amount of estrogen produced by the
           body by blocking an enzyme called aromatase. Each of these drugs have been approved by
           the FDA for this cancer and have been used in the treatment of metastatic ER-positive
           breast cancer for many years.

        -  In this part of the research study the investigators are looking for the safest doses of
           these drugs to give to participants at the same time.

        -  The overall goal of this study is to evaluate the safety and effectiveness of Tucatinib
           in combination with Abemaciclib, Trastuzumab, and hormonal therapy for hormone
           receptor-positive, HER2-positive Metastatic Breast Cancer
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalTucatinib is administered orally twice daily Abemaciclib is administered orally twice daily Trastuzumab is adminidtered intravenously once every three weeks Aromatase Inhibitor is administered orally once daily
  • Tucatinib
  • Abemaciclib
  • Trastuzumab
  • Aromatase Inhibitor
Arm A: Active Brain MetastasesExperimentalTucatinib is administered orally twice daily Abemaciclib is administered orally twice daily Trastuzumab is adminidtered intravenously once every three weeks Aromatase Inhibitor is administered orally once daily
  • Tucatinib
  • Abemaciclib
  • Trastuzumab
  • Aromatase Inhibitor
Arm B: Surgical Resection NeededExperimentalTucatinib is administered orally twice daily Abemaciclib is administered orally twice daily Trastuzumab is adminidtered intravenously once every three weeks Aromatase Inhibitor is administered orally once daily
  • Tucatinib
  • Abemaciclib
  • Trastuzumab
  • Aromatase Inhibitor
Arm C: Progressive Extracranial DiseaseExperimentalTucatinib is administered orally twice daily Abemaciclib is administered orally twice daily Trastuzumab is adminidtered intravenously once every three weeks Aromatase Inhibitor is administered orally once daily
  • Tucatinib
  • Abemaciclib
  • Trastuzumab
  • Aromatase Inhibitor

Eligibility Criteria

        Inclusion Criteria:

        Dose Escalation Cohort:

          -  At least one measurable or non-measurable metastasis by radiographic evaluation or
             physical examination.

          -  Progressive breast cancer on most recent regimen

          -  Presence of CNS metastases allowed, but not required for participation in the dose
             escalation cohort.

        Expansion Cohort A:

          -  At least one measurable CNS metastasis per RANO-BM, defined as ≥ 10 mm in at least one
             dimension.

          -  Unequivocal evidence of new and/or progressive brain metastases, and at least one of
             the following scenarios:

          -  Treated with SRS or surgery with residual un-treated lesions remaining. Such
             participants are eligible for immediate enrollment on this study providing that at
             least one untreated lesion is measurable

          -  Participants who have had prior WBRT and/or SRS and then whose lesions have
             subsequently progressed are also eligible. In this case, lesions which have been
             treated with SRS may be considered as target lesions if there is unequivocal evidence,
             in the opinion of the treating physician, of progression following SRS.

               -  Participants who have not previously been treated with cranial radiation (e.g.,
                  WBRT or SRS) are eligible to enter the study, but such participants must be
                  asymptomatic from their CNS metastases and not requiring corticosteroids for
                  symptom control.

               -  Both participants who present with systemic stable/absent or systemic progressive
                  disease are eligible, as long as they fulfill one of the above criteria.

        Expansion Cohort B:

          -  New and/or progressive brain metastasis(es) with clinical indication for surgical
             resection.

          -  Participants must have evaluable intracranial disease according to RANO-BM prior to
             surgical resection. Should participants also have extracranial disease, it may be
             evaluable according to RECIST 1.1

        Expansion Cohort C:

        -At least one measurable extracranial metastasis according to RECIST 1.1

        All Cohorts:

          -  Pathologically confirmed Hormone Receptor (HR)-positive HER2-positive MBC by local
             laboratory with the following requirements:

               -  To fulfill the requirement of HR-positive disease, the most recent biopsy
                  (primary tumor or metastatic lesion) of the breast cancer must express at least
                  one of the hormone receptors (estrogen receptor [ER] or progesterone receptor
                  [PR]) by immunohistochemistry (IHC). ER and PR assays are considered positive if
                  there are > 1% positive tumor nuclei in the sample.

               -  To fulfill the requirement of HER2-positive disease, the most recent biopsy
                  (primary tumor or metastatic lesion) of the breast cancer must demonstrate HER2
                  overexpression or amplification (immunohistochemistry of 3+ or HER2 gene
                  amplification by in situ hybridization with a ratio of HER2-gene signals to
                  centromere 17 signals ≥ 2.0 or average HER2 copy number ≥ 6.0 signals/cells).

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          -  Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (echo) or multigated
             acquisition (MUGA) scan within 3 months before initiation of study treatment. Patients
             with a history of LVEF < 50% should have left ventricular ejection fraction (LVEF) ≥
             50% by echocardiogram (echo) or multigated acquisition (MUGA) scan within the
             screening window.

          -  Stable or decreasing corticosteroid dose for at least 7 days prior to initiation of
             treatment.

          -  Concurrent administration of other anti-cancer therapy during the course of this study
             is not allowed, except for hormonal therapy with one of the commercially available
             aromatase inhibitors (AI) and the use of ovarian suppression in pre-menopausal
             patients. Note that concurrent use of supportive care medications (e.g.
             anti-resorptive agents, pain medications) is allowed. Pre-menopausal patients will
             need to receive ovarian suppression with the use of one of the commercially available
             GNRH agonists, per the choice of the treating physician.

          -  The subject is ≥18 years old.

          -  Participants must have normal organ and marrow function as defined below:

          -  Absolute neutrophil count ≥ 1.5 × 109/L

               -  Platelets ≥ 100 × 109/L

               -  Hemoglobin ≥ 8 g/dL

          -  Note: Patients may receive erythrocyte transfusions to achieve this hemoglobin level
             at the discretion of the investigator. Initial treatment must not begin earlier than
             the day after the erythrocyte transfusion.

               -  Total bilirubin ≤ 1.5 × ULN.

               -  Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and
                  direct bilirubin within normal limits are permitted;

               -  AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional ULN.

               -  Albumin > 2.5mg/dL

               -  Serum creatinine ≤ 1.5 × ULN.

          -  Female subjects of childbearing potential must have a negative serum or urine
             pregnancy test prior to initiating protocol therapy.

          -  The effects of tucatinib, abemaciclib, and trastuzumab on the developing human fetus
             are unknown so women of child-bearing potential and men must agree to use adequate
             contraception (barrier method of birth control; abstinence) prior to study entry and
             for the duration of study participation and 4 months after completion of tucatinib and
             abemaciclib administration and 7 months after trastuzumab administration.

          -  The subject is capable of understanding and complying with the protocol and has signed
             the informed consent document.

          -  Participant must be able to swallow and retain oral medication.

          -  Have discontinued all previous therapies for breast cancer (including chemotherapy,
             radiotherapy, immunotherapy, and investigational therapy), except for trastuzumab, for
             at least the following number of days prior to receiving study drug(s):

               -  28 days for myelosuppressive agents given every 28-day schedule.

               -  21 days for myelosuppressive agents given every 21-day schedule.

               -  14 days for myelosuppressive agents given every 7-day schedule, or for oral
                  agents or for nonmyelosuppresive agents

          -  Patients must have recovered from the acute effects of therapy (until the toxicity
             resolves to either baseline or at least Grade 1) except for residual alopecia or
             peripheral neuropathy

        Exclusion Criteria:

          -  Visceral crisis or impending visceral crisis at time of screening.

          -  CNS complications for whom urgent neurosurgical intervention is indicated (e.g.,
             resection, shunt placement).

          -  Known leptomeningeal metastases [Defined as positive CSF cytology and/or unequivocal
             radiological evidence of clinically significant leptomeningeal involvement. CSF
             sampling is not required in the absence of suggestive symptoms to exclude
             leptomeningeal involvement].

          -  Patients unable to undergo gadolinium contrast-enhanced MRI or receive IV gadolinium
             contrast for any reason (e.g., due to pacemaker, ferromagnetic implants,
             claustrophobia, extreme obesity, hypersensivity).

          -  Has received prior therapy with a CDK4/6 inhibitor.

          -  No washout is required for endocrine therapy. If a patient has been on ovarian
             suppression for at least 28 days prior to study entry, ccontinuation of ovarian
             suppression is permitted on protocol. Patients can receive a new form of endocrine
             therapy with one of the commercially available AIs at the time of initiation of
             protocol therapy.

          -  Subjects with a history of grade 3 or 4 allergic reactions attributed to compounds of
             similar biologic composition to tucatinib and/or abemaciclib or any constituent of the
             product(s).

          -  The subject has an uncontrolled intercurrent illness, including, but not limited to,
             ongoing or active infection, uncontrolled hypertension, unstable angina pectoris,
             uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association
             Class III or IV, active ischemic heart disease, myocardial infarction within the
             previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration
             diagnosed within the previous 6 months, chronic liver or renal disease, or severe
             malnutrition.

          -  The subject is pregnant or breast-feeding.1No active, second potentially
             life-threatening cancer. Exceptions include non-melanoma skin cancers, curatively
             treated in situ cancer of the cervix, DCIS, stage1/grade 1 endometrial carcinoma.

          -  Has had major surgery within 21 days before treatment initiation.

          -  Active infection requiring iv antibiotics at the time of treatment initiation.

          -  Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,
             resulting in dyspnea at rest.

          -  Known intolerance to trastuzumab.

          -  Patients may not be receiving concurrent therapy with strong inhibitors of CYP3A4 or
             strong inhibitors or inducers of CYP2C8. Please refer to Appendix M for a list of
             inhibitors and inducers. Please note that concurrent use of trimethoprim, a component
             of Bactrim, is prohibited per protocol. Patients who require PCP prophylaxis will need
             to switch to an alternative antibiotic (e.g. mepron)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The Maximum Tolerated Dose
Time Frame:2 years
Safety Issue:
Description:Determine recommended MTD for phase 2 combination of tucatinib with abemaciclib and trastuzumab.

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:20 year
Safety Issue:
Description:Efficacy of study combination, defined by CNS ORR according to RANO-BM.
Measure:Duration of Response
Time Frame:2 years
Safety Issue:
Description:DOR in the CNS according to RANO-BM.
Measure:Extracranial ORR
Time Frame:2 Years
Safety Issue:
Description:Extracranial ORR according to RECIST 1.1.
Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:Bi-compartmental progression-free survival (PFS) according to RANO-BM.
Measure:Duration of Extracranial Response
Time Frame:2 Years
Safety Issue:
Description:Duration of Extracranial Response according to RANO-BM.
Measure:Overall Survival
Time Frame:2 Years
Safety Issue:
Description:OS will be analyzed using Kaplan-Meier product-limit estimates and 90% confidence bands
Measure:Site of First Progression
Time Frame:2 Year
Safety Issue:
Description:Site of First Progression, CNS vs extracranial vs both
Measure:Extra-CNS response rates
Time Frame:2 years
Safety Issue:
Description:Extra-CNS response rates according to RECIST 1.1
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time Frame:2 years
Safety Issue:
Description:to evaluate the number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Breast Cancer

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